Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (The CANVAS Program)

Background: Sodium-glucose Co-transporter2 (SGLT2) inhibitors have shown promise in reducing the risk of cardiovascular (CV) death in patients with type 2 diabetes. The EMPA-REG trial of empagliflozin (Jardiance®) was an exciting development for diabetes management, as it showed that this medication minimized CV risk. The CANVAS Program sought to prove similar efficacy for canagliflozin (Invokana®) in reducing CV and renal risk.

The CANVAS Program was comprised of two double-blind, randomized, placebo-controlled studies developed to test the non-inferiority [HR below 1.3] of canagliflozin to placebo. The first study, CANVAS, started in 2009. Data from CANVAS was “unmasked” and included in regulatory filing documents for FDA approval for canagliflozin; thus, a new trial was needed to continue studying the drug. Therefore, CANVAS-R started in 2014 to explore canagliflozin’s renal effects and ongoing CV impact.

Purpose: The primary outcome was a composite of death from CV causes, nonfatal myocardial infarction, or non-fatal stroke. Secondary outcomes were death from any cause, death from CV causes, progression of albuminuria (30% increase and change in albuminuria status) and the composite of death from CV causes and hospitalization for heart failure.

Study Design: The studies included patients with type 2 diabetes who had an A1c between 7% and 10.5%. Patients were included if they were 30 years or older with a history of symptomatic atherosclerotic CV disease or if they were 50 years or older with two or more risk factors for CV disease (diabetes for at least 10 years, SBP ≥140 mm Hg on antihypertensive(s), current smoker, microalbuminuria or macroalbuminuria, or HDL < 38.7 mg/dL). Patients were excluded if they had an eGFR < 30 mL/min/1.73m2, a history of diabetic ketoacidosis, type I diabetes, pancreas or beta-cell transplant, history of one or more hypoglycemic episodes, or inadequately controlled thyroid disorder.

Of note, canagliflozin patients showed an increased rate of amputations at 6.3 vs 3.4 amputations per 1000 patient years (HR 1.97 [95% CI 1.41-2.75]). 71% of amputations were at toe or metatarsal and the highest risk of amputation was among patients with a history of amputation or peripheral vascular disease (PVD). Fracture rate was also higher with canagliflozin, occurring at a rate of 15.4 vs 11.9 fractures per 1000 patient years (HR 1.26 [95% CI 1.04-1.52]).

Conclusions: Canagliflozin reduced the frequency of the primary endpoint of composite death from CV causes, non-fatal MI, and non-fatal stroke. It also slowed the progression of albuminuria compared with placebo. However, it showed an increased risk of amputation in patients with a history of amputations or PVD.

Key Point: The CANVAS Program studies support that CV benefits are a class effect for SGLT2 inhibitors. However, the increased risk of amputation may lead clinicians to steer towards other SGLT2s.